The invention relates to opening of the blood-brain barrier, and more particularly to noninvasive techniques for doing so.
Ultrasound systems transmit energy at ultrasound frequencies into a desired subject. The signals can be detected and processed to produce images of the subject. The signals can also be concentrated or focused in such a way as to ablate, or induce cavitation in, a selected region of the subject. For any of these uses, an array of transducers is often used to provide the signals, and to focus the ultrasound energy in a desired manner to either image the subject or to ablate or otherwise provide ultrasound therapy to the subject. By using ultrasound, regions of a patient""s body can be imaged or treated in a noninvasive manner, reducing cost and risk to the patient, especially when imaging or treating sensitive areas of the patient such as the brain.
The blood vessels in the brain include endothelial cells connected by xe2x80x9ctight junctionsxe2x80x9d in what is known as the Blood-Brain Barrier (BBB). The BBB inhibits substances in the blood flow of a subject from entering the subject""s brain. While this is often desirable, e.g., by reducing illness, it is often a nuisance, e.g., by inhibiting delivery of drugs to the brain to help, not hinder, the subject. For example, in spite of a large number of very potent drugs, many central nervous system diseases are difficult to treat due to the inability of these substances to penetrate the BBB. Similarly, the BBB is a major limitation for genetherapy in the brain. Some other organs also contain tight junctions that limit drug delivery. Thus, the body contains multiple blood-organ barriers.
Various options for opening the BBB are available. Drugs can be made to penetrate the BBB, e.g., by making the drugs lipophilic, or by using carriers such as amino acid and peptide carriers. Another option is to physically open the BBB tight junctions temporarily. Chemicals can be administered to the brain to open the tight junctions of the BBB. For example, osmotic opening is possible using an intra-carotid arterial injection of hypertonic solution to shrink the endothelial cells and open the tight junctions. Drug xe2x80x9ccocktailsxe2x80x9d may also open the BBB, and may do so in a more time-controlled manner than osmotic opening. In both the osmotic and chemical opening techniques, an intra-arterial catheter insertion is used and the BBB in the whole brain opens. More localized opening can be achieved by inserting a catheter into the brain and infusing an opening agent directly to a targeted area.
In general, in an aspect, the invention provides a method of opening a blood-organ barrier of a subject. The method includes providing an exogenous agent configured to facilitate opening of the blood-organ barrier, administering the exogenous agent to a desired region of the subject, and applying energy to the desired region of the subject while the exogenous agent is present in the desired region, the energy being in a blood-organ-barrier-opening amount sufficient to induce opening of the blood-organ barrier of the subject with the exogenous agent present and below a damage amount sufficient to induce thermal damage to tissue in the absence of the exogenous agent.
Implementations of the invention may include one or more of the following features. The energy applied is ultrasound energy and the exogenous agent contains at least one of gaseous bubbles, a high concentration of gas, solid particles configured to vaporize in response to body temperature, solid particles configured to vaporize in response to the ultrasound energy, liquid configured to vaporize in response to body temperature, liquid configured to vaporize in response to the ultrasound energy, micro particles configured to act as cavitation sites, solid particles having higher acoustic impedance than tissue in the desired region, and liquid with a high acoustic absorption coefficient. The blood-organ-barrier-opening amount is less than approximately one order of magnitude lower than the damage amount. The blood-organ-barrier-opening amount is less than approximately two orders of magnitude lower than the damage amount.
Implementations of the invention may further include one or more of the following features. The exogenous agent is administered to the subject without penetrating a skull of the subject. The exogenous agent is administered through a vasculature of the subject. The administering includes waiting for the exogenous agent to reach the desired region via the vasculature.
Implementations of the invention may further include one or more of the following features. The method further includes imaging at least the desired region of the subject and determining if the blood-organ barrier has opened in the desired region using results of the imaging. The applying includes adjusting at least one characteristic of the ultrasound energy to apply at least the blood-organ-barrier-opening amount to the desired region.
Implementations of the invention may further include one or more of the following features. The exogenous agent contains preformed bubbles that have a mean diameter less than an upper size limit for being able to pass through a capillary bed of the subject. The exogenous agent has a concentration of bubbles high enough such that the blood-organ barrier will open in response to the applied energy.
In general, in another aspect, the invention provides a method of opening a blood-brain barrier of a subject. The method includes providing an exogenous agent configured to facilitate opening of the blood-organ barrier, administering the exogenous agent to a desired region of a brain of the subject, and applying ultrasound energy to the desired region of the brain of the subject while the exogenous agent is present in the desired region, the ultrasound energy being in a blood-brain-barrier-opening amount sufficient to induce opening of the blood-brain barrier of the subject with the exogenous agent present, the blood-brain-barrier-opening amount being below a damage amount sufficient to induce thermal damage to brain tissue of the subject, and the exogenous agent being administered to the subject in a non-invasive manner relative to a skull of the subject.
Implementations of the invention may include one or more of the following features. The blood-brain-barrier-opening amount is less than approximately two orders of magnitude lower than the damage amount. The exogenous agent contains preformed gaseous bubbles. The energy applied is ultrasound energy and the exogenous agent contains at least one of a high concentration of gas, solid particles configured to vaporize in response to body temperature, solid particles configured to vaporize in response to the ultrasound energy, liquid configured to vaporize in response to body temperature, liquid configured to vaporize in response to the ultrasound energy, micro particles configured to act as cavitation sites, solid particles having higher acoustic impedance than tissue in the desired region, and liquid with a high ultrasound absorption coefficient.
In general, in another aspect, the invention provides a method of opening a blood-brain barrier of a subject, the method including providing an exogenous agent containing gaseous bubbles, administering the exogenous agent to a desired region of a brain of the subject, applying ultrasound energy to the desired region of the brain of the subject while the exogenous agent is present in the desired region, the ultrasound energy being in a blood-brain-barrier-opening amount sufficient to induce opening of the blood-brain barrier of the subject with the exogenous agent present, imaging at least the desired region of the brain of the subject, and determining if the blood-brain barrier has opened in the desired region using results of the imaging, the blood-brain-barrier-opening amount is below a damage amount sufficient to induce thermal damage to brain tissue of the subject, and the exogenous agent is administered to the subject in a non-invasive manner relative to a skull of the subject.
Implementations of the invention may include one or more of the following features. The applying includes adjusting at least one characteristic of the ultrasound energy to apply at least the blood-brain-barrier-opening amount to the desired region. The blood-brain-barrier-opening amount is less than approximately two orders of magnitude lower than the damage amount. The exogenous agent contains preformed bubbles that have a mean diameter less than an upper size limit for being able to pass through a capillary bed of the subject. The exogenous agent has a concentration of bubbles high enough such that the blood-brain barrier will open in response to the applied energy.
Various aspects of the invention may provide one or more of the following advantages. Ultrasound can be used to produce consistent focal blood-brain barrier opening leakage substantially without damage to surrounding brain tissue while using noninvasive image guidance and monitoring. Temporal average spatial peak powers of approximately two orders of magnitude below the level required for thermal damage of the brain tissue can be used while opening the blood-brain barrier (BBB). Local noninvasive targeted drug delivery, cell transplantation, gene therapy, or delivery of other substances with therapeutic or diagnostic use can be achieved in the brain or other organs in which drug delivery via the vasculature is limited. Undesired effects to non-targeted issues may be reduced and/or eliminated.
These and other advantages of the invention, along with the invention itself, will be more fully understood after a review of the following figures, detailed description, and claims.